Abstract In this Supplement, we will be investigating whether the BDNF prodomain with a human SNP has biological activity within the AD brain, based on the premise that the prodomain and its co- receptors (p75NTR and SorCS2) are up-regulated in the AD brain. The ongoing scope of this grant has focused on a developmental period, peri-adolescence, when this ligand and receptor complex initially are co-expressed in the hippocampus. These proposed studies in the AD mouse model will assess whether the in vivo biological activity of the BDNF prodomain contributes to the altered neuronal and behavioral phenotypes in an AD mouse models at a later developmental time point. These proposed studies would suggest a reconceptualization of the biological role of this growth factor in AD that has been previously focused on loss of the mature form of BDNF leading to altered neuronal function in AD.